The EGF receptor (EGFR), the biological receptor of EGF and TGF-α is frequently over-expressed in oral cancers. The binding of the ligands to EGFR causes auto-phosphorylation of certain tyrosines on EGFR and thereby triggers a cascade of signal transduction events. Increased expression of EGF receptor in oral cancers is associated with aggressiveness of the tumors. The EGFR also directly interacts with β-catenin and the EGFR-induced tyrosine phosphorylation ofβ-catenin causes dysfunction of the E-cadherin–mediated cell adhesion in cancer, resulting in increased cell motility, invasion, and metastasis. Therefore, targeted blockage of the EGFR-β-catenin signaling pathway is critical in the prevention of tumor aggressiveness. The transcriptional repressor HBP1 is a documented G1 inhibitor in both cell culture and animal models. HBP1 represses a number of growth regulatory genes (e.g. N-Myc, c-Myc, and Cyclin D1). More importantly, HBP1 is shown to be an inhibitor of the Wnt/β-catenin signaling pathway, which is involved in many cancer types. Several studies have linked the production of reactive oxygen species (ROS) by the NADPH oxidase to cellular growth control. In many cases, activation of the NADPH oxidase and subsequent ROS generation is required for growth factor signaling and mitogenesis in non-immune cells. It has been recently demonstrated that HBP1 regulates the gene for the p47phox regulatory subunit of the NADPH oxidase. Current work would focus on the hypothesis that HBP1 represses growth-factor dependent signal transduction through inhibition of growth factor-induced ROS generation, increased PTP activity and a concomitant decrease in ligand-induced EGFR-β-catenin signal transduction in oral cancers. To test this hypothesis, we will use the RNAi technique to knockdown HBP1 in oral cancer cell lines and assay for the EGFR-β-catenin signaling, the epithelial-mesenchymal transitions(EMT), and cell migration and invasiveness. These investigations should provide a molecular foundation for new biomarkers in the design of specific clinical diagnosis strategies.
